Vascular endothelial growth factor (VEGF) is a cytokine involved in angiogenesis. The ligand VEGF-A interacts with VEGF receptor-1 (VEGFR1) and VEGFR2, thereby initiating an angiogenesis signaling pathway in normal and tumor vasculature. Antagonists of VEGF are known to be useful for the treatment of a variety of diseases and disorders including cancers, eye diseases and other conditions involving excessive, unwanted or inappropriate angiogenesis. An example of a VEGF antagonist is aflibercept (also known as VEGF Trap; marketed as ZALTRAP®, Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.). Aflibercept is a VEGF receptor-based chimeric molecule comprising domain 2 from VEGFR1 fused to domain 3 from VEGFR2, which is, in turn, attached through the hinge region to the Fc(a) domain of human IgG1. Aflibercept is approved for the treatment of colorectal cancer and is being developed for the treatment of other cancerous conditions as well. VEGF Trap is described, e.g., in U.S. Pat. No. 7,070,959; see also, Holash et al., Proc. Natl. Acad. Sci. USA 99:11393-11398 (2002).
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a member of the immunoglobulin superfamily of proteins and is involved in negative regulation of T-cell activation. Upon T cell activation, CTLA-4 is upregulated and competes with CD28 for binding to B7, thereby transmitting a suppressive signal for T cell activation. Antibodies against CTLA-4 have been shown to block the interaction between CTLA-4 and the costimulatory molecules B7.1 and B7.2 (CD80 and CD86). This blockade removes the CTLA-4-mediated inhibitory signal on T-cells and thereby stimulates a natural immune response against cancer cells. Anti-CTLA-4 antibodies have been shown to be clinically effective in the treatment of, e.g., metastatic melanoma. Exemplary anti-CTLA-4 antibodies include ipilimumab (Yervoy®, Bristol-Myers Squibb, disclosed in U.S. Pat. No. 6,984,720) and tremelimumab (Pfizer, disclosed in U.S. Pat. No. 8,491,895).
Although VEGF antagonists and anti-CTLA-4 antibodies have individually shown great promise in the treatment of tumors and other cancerous conditions, more directed, potent and sustained therapeutic options are nonetheless needed for the effective treatment of such diseases and disorders. Accordingly, an unmet need exists in the art for novel therapeutic approaches for the treatment of cancer.